(a) Field of Invention
This invention relates to novel 2-aminomethylalkynylalkyl-1,3-dithiane derivatives, their pharmaceutically acceptable salts and their use in cardiovascular and gastrointestinal disorders in which calcium channel entry blockers are effective.
(b) State of the Art
Calcium ions apparently play a ubiquitous role in physiological body functions. They are involved in blood clotting and coagulation, cellular adhesion and integrity, membrane stability, enzyme activity, mediation of some of the effects of prostaglandins, neuronal transmission, glandular and cellular secretory functions, muscle contractions and many other physiological actions. Agents that act as calcium antagonists have a wide variety of therapeutic applications, e.g., as antihypertensives, coronary dilators, antiarrhythmics, smooth and skeletal muscle relaxants, antiinflammatory agents and local anesthetics, for example [R. G. Rahwan, M. F. Piasak, and D. T. Witiak, Canad. J. Physiol. Pharmacol., 57, 443 (1979); R. G. Rahwan and D. T. Witiak. in "Trace Metals in Health and Disease", N. Karasch, Ed., Raven Press, New York, p. 217]. These drugs are of particular value in the treatment of cardiac oxygen-deficiency diseases especially various forms of angina pectoris [H. Meyer, Annu. Rep. Med. Chem., 17, 71-77 (1982)]. Most of these agents are important cardiovascular drugs that inhibit smooth and cardiac muscle contraction. Comprehensive surveys of the pharmacology and potential therapeutic uses of calcium channel blockers have appeared [E. Wehinger and R. Gross, Annu. Rep. Med. Chem., 21, 85-94 (1986)].
The calcium channel blockers act mainly by inhibiting the influx of extracellular calcium into cells through the so-called "slow-calcium channel" in the cell membrane. Although inhibition of the slow inward calcium current is common to all calcium entry blockers, these agents often possess other major pharmacological actions that likely contribute to the overall effects [R. G. Rahwan, D. T. Witiak, and W. M. Muir, Annu. Rep. Med. Chem., 16 257-268 (1981)]. Thus .beta..sub.2 -adrenergic receptors with calcium channel blocking activity increase levels of smooth muscle cyclic-AMP, thus enhancing their smooth muscle relaxing properties (W. C. Bowman and M. J. Rand, "Textbook of Pharmacology", 2nd ed., Blackwell, Oxford. 1980. p. 22: 7). Among certain antiinflammatory drugs, calcium antagonistic actions correlate with their ability to inhibit prostaglandin synthesis associated with this property [B. J. Northover, Gen. Pharmacol., 8, 293 (1977)]. Indeed, the widely used antidiarrheal drug loperamide binds to calcium antagonist sites and it has been suggested that a substantial part of its therapeutic effectiveness is due to blockade of voltage-sensitive calcium channels in intestinal mucosal and smooth muscle cells [I. J. Reynolds, R. J. Gould and S. H. Snyder, J. Pharmacol. Exp. Ther., 231(3), 628-632 (1984)]. Thus, novel, selective, tissue specific calcium channel antagonists have potential utility as antidiarrheal and antispasmodic treatments for irritable bowel disease.
The majority of presently known calcium channel antagonists are structurally similar to four distinct classes of organic compounds, e.g., verapamil and its analogs, the dihydropyridines (e.g., nitrendepine), the benzothiazepines (e.g., diltiazem), and the diphenylalkylamines (e.g., cinnarazine). Apparently these disparate groups of compounds reduce smooth muscle contractility and secretory processes through either competitive interactions with a calcium channel site (receptor) or through sites allosterically linked to the channel [M. Spedding, M. Gittos, and A. K. Mir, J. Cardiovas. Pharmacol., 9, 461-468 (1987); A. K. Mir and M. Spedding, J. Cardiovas. Pharmacol., 9, 469-477 (1987)]. Completely new structures whose pharmacological action is primarily due to inhibition of calcium into contractile cells are relatively rare [H. Meyer, S. Kazda, and P. Bellemann, Annu. Rep. Med. Chem., 18, 79-88 (1983)].
The present invention provides a novel, structurally unique class of 2-aminomethylalkynylalkyl-1,3-dithiane derivatives which have calcium channel blocking activity.